Intravenous indometacin in preterm infants with symptomatic patent ductus arteriosus. A population pharmacokinetic study

British Journal of Clinical Pharmacology - Tập 58 Số 3 - Trang 249-258 - 2004
J. M. Smyth1, Paul S. Collier1, M Darwish1, Jeffrey S. Millership1, Henry L. Halliday2, S. Petersen3, James C. McElnay1
1Clinical and Practice Research Group, School of Pharmacy
2Department of Child Health, Queen's University, Belfast, UK
3Department of Neonatology and Paediatrics, Rigshospitalet, Copenhagen, Denmark

Tóm tắt

AimsTo characterize the population pharmacokinetics of indometacin in preterm infants with symptomatic patent ductus arteriosus and to investigate the influence of various factors on the response to treatment.MethodsData were collected from 35 infants (gestational age 25–34 weeks; postnatal age 1–77 days) in neonatal units in Belfast and Copenhagen. Infants received an initial course of up to three doses of intravenous indometacin (0.1–0.2 mg kg−1) as considered appropriate by the treating physician. For those infants who did not respond to therapy or in whom the ductus reopened, a second course was sometimes given. Population analysis of the 185 plasma concentrations obtained was conducted using NONMEM and pharmacokinetic and demographic differences between responders and nonresponders were compared.ResultsThe concentration‐time course of indometacin was best described by a one‐compartment model. The final population parameter estimates of clearance (CL) and volume of distribution (V) (standardized to the median weight of 1.17 kg) were 0.00711 l h−1 and 0.266 l, respectively. CL increased from birth by approximately 3.38% per day and V by approximately 1.47% per day. Concomitant digoxin therapy resulted in a 30% decrease in V. Interindividual variability in CL and V was 41% and 21%, respectively. Interoccasion variability for CL was 43%. Residual variability corresponded to a standard deviation of 0.148 mg l−1. Closure occurred in 75% of infants with a plasma concentration ≥ 0.4 mg l−1 24 h after the last dose.ConclusionsDosing regimens for indometacin should take into account the weight and postnatal age of the infant and any concomitant digoxin therapy. The population estimates can be used to determine typical values of CL and V allowing the prediction of individualized doses of indometacin that should increase the probability of achieving a 24 h plasma concentration ≥ 0.4 mg l−1. Although the pharmacokinetic estimates will be affected by both interindividual and within‐individual variation, it is anticipated that this approach will decrease the variability of exposure and optimize treatment outcome.

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British Journal of Clinical Pharmacology

Tập 58 Số 3

249-258

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